Agent for inducing hair growth containing extracts of saw palmetto and swertia

ABSTRACT

The present invention consists in a composition comprising a mixture of extracts of saw palmetto and  swertia , of derivatives thereof and of active components being part of said extracts. The composition may comprise additional agents and/or extracts, for example, irritating agents, extracts for hair invigoration, hair nourishment agents, antidandruff antiproliferative compounds, extracts with an antimicrobial, extracts with an antifungal, extracts with anti-inflammatory agents, extracts with a steroid, extracts with a nitric oxide donor and extracts with minoxidil. The concentration of the saw palmetto extract in the composition is suitably 0.01–100%. The composition may comprise a suitable carrier, solvent and/or emulgent. The composition may be, for example, an internally ingested tablet, a capsule, drops or a suspension. The invention relates also to the use of said composition in the preparation of a mixture for the application to humans and animals against the loss of hair and to method for the treatment with said composition for the treatment of humans and animals against loss of hair.

The present invention relates to plant extracts useful as modulators ofhair growth during conditions of hair loss.

Normal scalp hair loss can be caused either by a physiologic pattern ofaging or to a genetically controlled trend of non-scarring hair loss,named androgenetic alopecia. The hair loss of aging evolves as a slowprocess in middle-aged and elderly subjects, as a generally diffusegradual and progressive hair thinning and loss from most of the hairyscalp. Contrary to the previous etiology, androgenetic alopecia developsearlier, even in 18 years old subjects, develops rapidly and involvesspecific temporal hair loss in male type, or vertex hair loss of femaletype androgenetic alopecia. In addition to the physiologic hair loss,various etiologies may cause hair deprivation, e.g. immune diseases(alopecia areata), pharmacological drugs (heparin, lithium) or diseases(fungal).

Generally, the hair follicle and resulting hair shaft are in continuousgrowth and involution, and develop in three general stages: anagen, thegrowth phase of about 3 years, catagen, a transitional 3 weeks phase ofdevelopment preceding the catagen phase, an involution of the hairfollicle lasting about 3 months, afterwards the hair starts its cycleagain.

Various treatments were suggested for hair loss, such as

-   -   i) Topical minoxidil (U.S. Pat. No. 4,596,812) at concentrations        from 1–5%, with an improvement in hair loss in about ⅓–⅔ of        patients (Koperski et al, 1987). At the more effective higher        concentrations, it cannot be used in women and may cause        hypotension or hypertrichosis.    -   ii) A relatively new indication for the antiprostatic drug        Finasteride (U.S. Pat. No. 4,760,071), improves hair loss after        at least one-year daily uptake of the drug. Claims a 60% success        as compared with 39% hair growth in control group, but without        broad clinical evidence of efficacy and side effects, i.e.        impotence.    -   iii) A variety of plant extracts were proposed as hair growths        stimulants. Most of the data has not published in peer reviewed        medical literature. Part of it is referred in various patents,        e.g. U.S. Pat. Nos. 5,750,107 and 4,769,231, and European Patent        EP 584365. Said plant extracts are, for example, grape seed,        ginseng, jojoba, kola, lavender, swertia, guarana or saw        palmetto.    -   iv) Other remedies, which possess a low efficacy or cause high        side effects, are spironolactone, acetylcholine derivatives,        estradiol, nicotinic acid amide, nicotinic acid, benzyl        nicotinate, glycyrrhizinic acid, cyclosporin and prostaglandin        analogues.    -   v) Unproven treatments are those with Vitamin E, Vitamin B6,        biotin, pantothenic acid, amino acids such as arginine,        capronium chloride, hinokitiol, serine and methionine, organic        acids or oils.

Thus, an effective treatment of hair loss is required. The treatmentshould be effective at least as minoxidil, without having inherenthypotensive properties and be available for women as well. Preferably,the ideal treatment should not inflict the psychological effect oflong-term drug ingestion or induce low patient compliance due tolong-term use.

It has been discovered that the use of the mixture of extracts of sawpalmetto and swertia, derivatives thereof and of components being partof said extracts causes a surprising and unexpected synergistic effecton hair growth, even at minimal concentrations.

The present invention thus consists in a composition comprising amixture of extracts of saw palmetto and swertia, derivatives thereof andof components being part of said extracts.

The composition according to the present invention comprisesadvantageously the saw palmetto extract, from 0.01–100.0%, preferablybetween 0.1–50%, more preferably between 1.0–25% and optimally between2.5–25% by weight; and the swertia extract in a concentration from0.001–20.0%, preferably between 0.1–20%, more preferably between 0.2–5%and optimally between 0.25–2% by weight.

The composition according to the present invention may be topicallyapplied as such or internally ingested within a suitable carrier,solvent, dissolvent, emulgent, extract, solutions e.g. aqueous,alcoholic, oily, suspension; microemulsion, microcapsules, vesicles,etc.

The active agents may be formulated into various compositions, e.g. alotion, a conditioner, a hair tonic, a shampoo, a lotion withconditioner, a gel, a styling gel, a mousse, a styling wax, a mask, anaerosol, a moisturizer, a powder, a perfume, a brilliantine, a pomade, adye, a cream or an ointment.

The composition according to the present invention might be formulatedas well as an internally ingested tablet, capsule, drops or suspension.

The above composition can be used alone or in conjunction with:

-   -   1. Irritating agents, e.g. anthralin, retinol (Vitamin A) and        its derivatives, alpha-hydroxy acids, beta-hydroxy acids;    -   2. Extracts known for their hair revitalizing effect, e.g. aloe        vera, borage, chamomile, forsynthia, ginseng, grape seed,        guarana, jojoba, kola, lavender, nettle root, rosemary, pumpkin        seed, polygonum(Fo-Ti), pygeum, red clover, soy, tea tree oil        and thyme,    -   3. Hair nourishment agents, such as vitamins, e.g. tocopherol        (Vitamin E) and derivatives, Vitamin B6, biotin, pantothenic        acid, Vitamin D and its derivatives, Vitamin C; amino acids e.g.        arginine, citrulline, ornithine, serine and methionine; organic        acids, e.g. lactate or malate, minerals and metals, e.g. zinc        and its derivatives, magnesium, aluminum, death sea minerals;        eugenol, polyamines and antioxidants;    -   4. Low efficacy compounds such as spironolactone, acetylcholine        derivatives, estradiol, nicotinic acid amide, nicotinic acid,        benzyl nicotinate, cyclosporin, prostaglandin analogues;        glycyrrhizic acid and derivatives thereof;    -   5. Antidandruff anti proliferatives compounds, e.g. zinc        pyrithione, coal tar, selenium and its derivatives;    -   6. Antifungals, e.g. ciclopyroxolamine, piroctone olamine,        imidazoles (e.g. ketoconazole, bifonazole), metronidazole,        undecylenic acid and derivatives of the said compounds;    -   7. Antimicrobials, e.g. aluminium chloride, chlorothymol,        hexamine, zinc salyci late, zinc sulphide, triclorocarban,        triclosan;    -   8. Anti-inflammatory agents, e.g. bisabolol, panthenol or        cyclo-oxygenase inhibi tors;    -   9. Steroids, e.g. medicated low (hydrocortisone), intermediate        (mometasone) thigh (betamethasone, dexamethasone) potency        steroids, of plant origin, e.g. phytosterols;    -   10. Lipid derivatives, e.g. mineral oil, vegetable oil, animal,        synthetic oil, fatty alcohol, saturated and unsaturated fatty        acids, waxes and squalene;    -   11. Refrigerants, e.g. menthols;    -   12. Vasodilating compounds or nitric oxide donors, e.g. of        natural source (arginine) or medicated (nitroprusside); and    -   13. Finasteride or Minoxidil or an 5 alpha reductase inhibitor.        The amounts of said derivatives may be varied in accordance with        the specific requirements.

The composition according to the present invention may be prepared byconventional methods as becomes apparent from the Experiments givenhereinafter.

The present invention also consists in the use of the compositionaccording to the present invention in the preparation of a medicamentfor the treatment of humans and animals against loss of hair.

The present invention consists also in a method for the treatment forthe treatment of humans and animals against loss of hair with acomposition according to the present invention.

Data was objectively assessed by the experiments given hereafter in analready established hair growth model in mice [Inaoka Y, et al. 1994,42:530–3.], employing treatment versus controls. As a positive control,minoxidil 5% was used. Each extract did not affect the hair growth whenused alone in our model. However, when both compounds were combined, anincrease of hair growth of about 70% beyond baseline was quantified, aresult alike that of minoxidil 5%. The present invention thus fulfillsthe need for a natural combination of plant extracts and provides theadvantages of unanimous use and excellent efficacy.

In mice, the hair growth and effluvium are a continuous cyclic process.It was demonstrated that hair growth temporarily ceases at about 7weeks-old, for about 50 days. Therefore, any hair growth during thisperiod is non-physiologic and induced by external agents.Pharmacological agents applied during this stage, such as minoxidil orretinoids, were shown to induce hair growth (Bazanno, 1993). Anyresearch related to this model should employ minoxidil as the “goldenstandard” and as an essential positive control.

Mice (males, C3H type), which were in the resting phase in their haircycle, i.e. at 7 weeks of age, were employed in these experiments. Theskin of the back of the mice was subjected to a complete hair cut by anelectric razor, with areas of approximately 2.5×4 cm. Differentsolutions, as will be further described, (100 μL/day) were applied witha syringe 6 times a week for 18 days, and the skin was further massaged.At the end of the experiment, the animals were sacrificed and the skinof the back was excised. The excised skin was fixed on frame consistingof a metal disc with a radius of 0.9 cm. Hairs were cut by a scalpel,collected and weighted.

All formulations contained active ingredients (g/weight) as specified,20% ethanol and aqua distillata ad 100.0. Minoxidil was used as suppliedby the manufacturer (Pharmacia-Upjohn).

i. Control (placebo-treatment)

ii. Positive control—minoxidil 5% (Pharmacia-Upjohn)

iii. Saw Palmetto extract—7.5%

iv. Swertia extract—1%

v. Saw Palmetto —7.5% and Swertia 1% extracts

vi. Saw Palmetto —7.5% and Guarana 10% extracts

When synergism has to be demonstrated, one has to use low concentrationsof an expected active ingredient and show that each single agentapplication causes a modest effect, preferably none. In spite of this,the combination of non-active agents should exert a convincible positiveresult.

The results of said experiments are shown in Table I and FIG. 1 (datanot shown in FIG. 1 for group vi).

Table I shows the weighting results in miligrams, which reflect the hairgrowth in mice during a physiological resting phase of their hair cycle,i.e. without any expected hair growth.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 summarizes the stimulation of hair growth. Data represents hairweight and is given as percentages in comparison to control treatments.Controls and groups ii–v were treated by massaging the back of mice with20% ethanol in aqua distillata, or 20% ethanol in aqua distillata andactive ingredients, correspondingly.

TABLE 1 Weight Of Hair Standard Error of Treatment (mg) the Mean PControl (placebo) 2.52 0.08 Minoxidil 5.0% 4.07 0.44 P < 0.05 Palmetto7.5% 3.26 0.25 P = NS Swertia 1.0% 3.17 0.49 P = NS Palmetto 7.5% and4.34 0.16 P < 0.05 Swertia 1.0% Palmetto 7.5% and 3.02 0.25 P = NSGuarana 10.0%Statistical evaluation by Kruskal-Wallis One Way Analysis of Variance onRanks. The differences in the median values among the treatment groupsare greater than would be expected by chance; there is a statisticallysignificant difference (p=0.011) To isolate the group or groups thatdiffer from the others a multiple comparison procedure versus ControlGroup was used (Dunn's Method). Data was calculated by SigmaStat version2.0, Jandel.The Data in both Table 1 and in FIG. 1 are represented as percentages incomparison to control placebo-treated mice. The hair growth stimulationis demonstrated as compared to control of each group, in percentages asfollows:

-   -   1. The validity of the experimental setup is demonstrated by        comparison with a golden standard of minoxidil 5% which effects        an increase of hair weight of about 65% as compared to control        mice (p<0.05).    -   2. It is demonstrated that palmetto extract 7.5% did not cause        an increase of hair growth (p=non significant, NS)    -   3. It is demonstrated that swertia extract 1% did not caused an        increase of hair growth (p=NS)    -   4. However, the combination of extracts at concentrations of        swertia 1% and palmetto 7.5% resulted in an increase of hair        weight of 70% as compared to control mice (p<0.05)    -   5. A combination of palmetto 7.5% and guarana 10% extracts        (negative control) did not cause an increase of hair weight        (p=NS).

It is concluded that treatment of group v with a combination of sawpalmetto extract and swertia extract unexpectedly increase hair growth.The synergism is unequivocally specific for saw palmetto and swertiaextracts, since combination of saw palmetto with another allegedlyhair-stimulating extract at a low concentration, i.e. guarana, did notresult in synergism (negative control). The synergistic effects of sawpalmetto/swertia combination reflect a pharmacologically-inducedunexpected stimulation of hair growth.

The present invention will now be illustrated with reference to thefollowing Examples without being limited by them.

EXAMPLE 1

Hair Tonic Solution

INGREDIENT % Phase I w/w FUNCTION AQUA 69.0 ALCOHOL 20.0 Solvent,preserva- tive SAW PALMETTO EXTRACT 10.0 Active ingredient SWERTIAEXTRACT 1.0 Active ingredientManufacturing procedure:Mix all the components at room temperature.

EXAMPLE 2

Hair Clear Lotion

INGREDIENT % Phase I w/w FUNCTION AQUA 70.0 ALCOHOL 20.0 Solvent,preserva- tive SAW PALMETTO EXTRACT 7.5 Active ingredient SWERTIAEXTRACT 2.0 Active ingredient Phase II PERFUME 0.2 Fragrance PEG-40HYDROGENATED CASTOR OIL 0.3 Solubilizer (and) POLYSORBATE 20 (and)OCTOXYNOL-11Manufacturing Procedure:Mix all the components of the phase I at room temperature.Mix well the components of the phase II before adding on the phase I.

EXAMPLE 3

Hair Lotion with Conditioner

% INGREDIENT w/w FUNCTION ALCOHOL 39.0 Solvent, preserva- tivePOLYQUATERNIUM-2 1.5 Conditioner HYDROXYPROPYL GUAR 0.3 ConditionerHYDROXYPROPYLTRIMONIUM CHLORIDE DIMETHICONE COPOLYOL 1.0 Siliconesurfactant SAW PALMETTO EXTRACT 10.0 Active ingredient SWERTIA EXTRACT2.0 Active ingredient PERFUME 0.2 Fragrance AQUA 46.0Manufacturing procedure:Disperse the conditioner in the blend of water and polyquaternium—2.Add the alcohol, silicone, the extracts I and II and the fragrance. Mixto homogenous. Adjust the pH to 5–5.5

EXAMPLE 4

Hair Gel

% INGREDIENT w/w FUNCTION Phase I LAURYL GLUCOSIDE 4.0 Film formerHYDROLYZED COLLAGEN 1.5 Film former 1,2-PROPYLENGLYCOLE 3.0 MoisturizerPEG-40 HYDROGENATED CASTOR OIL 2.0 Solubilizer SAW PALMETTO EXTRACT 15.0Active ingredient SWERTIA EXTRACT 1.0 Active ingredient PHENOXYETHANOL(and) METHYL 0.3 Preservative PARABEN (and) ETHYL PARABEN (and) PROPYLPARABEN Phase II NaOH (10% water sol.) 3.0 Neutralizing agent EDTA tetrasodium 0.2 Chelating agent AQUA 14.8 CARBOMER (Carbopol 980) 2% swelling55.0 Gel former PERFUME 0.2 FragranceManufacturing Procedure:Mix the ingredients of the phase I, in the listed order at roomtemperature.Prepare the base gel of the phase II in the given order and add thephase I.Mix until homogenous and adjust the pH to 5–5.6 with NaOH sol.

EXAMPLE 5

Hair Styling Gel

% INGREDIENT w/w FUNCTION Phase I POLYVINYL PIROLIDONE (PVP K-30) 2.0Film former AQUA 20.0  Phase II ACRYLATE COPOLYMER (Capigel 98) 1.4 Gelformer AQUA 10.0  Phase III PEG-40 HYDROGENATED CASTOR OIL 0.3Solubilizer (and) POLYSORBATE 20 (and) OCTOXYNOL-11 SAW PALMETTO EXTRACT20.0  Active ingredient SWERTIA EXTRACT 2.0 Active ingredient PERFUME0.2 Fragrance Phase IV TRIETHANOLAMIN up to pH = 7.5 Qs Neutralizeragent PHENOXYETHANOL (and) METHYL 0.3 Preservative PARABEN (and) ETHYLPARABEN (and) PROPYL PARABEN (and) BUTYL PARABEN AQUA Up to 100.0 Manufacturing Procedure:Disperse the PVP in the water (phase I).Dilute the Capigel in the water (phase II).Dissolved the perfume and the Extracts in the solubilizer (phase III).Add Phase I to Phase II. Neutralize the gel with triethanolamin thanintroduce the preservative and the Phase Ill. Adjust the final pH to theoptimal range 7.2–7.5.Add water up to 100.0

EXAMPLE 6

Hair Styling Mousse

% INGREDIENT w/w FUNCTION Phase I CHITOSAN (Hydagen HCMF) 0.5 Stylingagent GLYCOLIC ACID 0.2 Solubilizer AQUA 78.5 Phase II POLYVYNILPYROLIDONE/VINYL 5.0 Gelling agent ACETATE COPOLYMER (PVP/VA 60:40)CETRIMONIUM CHLORIDE 1.0 Preservative HYDROLYZED WHEAT GLUTEN 3.0 Filmformer HYDROLYZED WHEAT PROTEIN SAW PALMETTO EXTRACT 10.0 Activeingredient SWERTIA EXTRACT 1.5 Active ingredient PERFUME 0.3 FragranceManufacturing Procedure:Add and mix the components listed under phase I till is homogenous.Add ingredients of phase II one by one and keep the pH-value bellow 6.Adjust the pH value to 4.0.

EXAMPLE 7

Hair Styling Wax

% INGREDIENT w/w FUNCTION Phase I GLYCERYL STEARATE 5.0 ThickenerCETEARETH-12 1.0 Emulsifier o/w DECYL OLEATE 5.0 Emollient PARAFFIN OIL10.0 Emollient Phase II CHITOSAN 0.8 Styling agent GLYCOLIC ACID 0.4Solubilizer AQUA 53.7 Phase III SAW PALMETTO EXTRACT 20.0 Activeingredient SWERTIA EXTRACT 1.5 Active ingredient CETRIMONIUM CHLORIDE40% 2.5 Preservative PERFUME 0.1 FragranceManufacturing Procedure:Heat the ingredients listed under phase I at 80–85° C. and mix tohomogenous. Mix the ingredients listed under phase II at roomtemperature till a homogenous solution is obtained. Heat the solution to80–850° C. and add to the phase I under continuous stirring.Cool down the emulsion to approx. 50–55° C. and add the ingredient ofthe phase III. Fill up hot in the commercial package.

REFERENCES CITED

Patents

-   U.S. Pat. No. 4,596,812, 6/1986, Chidsey, et al,-   U.S. Pat. No. 4,760,071, 7/1988, Rasmusson, et al.-   U.S. Pat. No. 5,750,107, 5/1998, Nomura, et al.-   U.S. Pat. No. 4,769,231, 9/1988, Ogura, et al.-   EP 584365, 3/1994, Murayama    Articles-   Bazzano G, et al. Effect of retinoids on follicular cells. J Invest    Dermatol 1993 Jul 101:1 Suppl 138s⁻¹⁴²S-   Inaoka Y, et al., Studies on active substances in herbs used for    hair treatment. Chem Pharm Bull (Tokyo). 1994, Mar;42(3):530 –3.-   Koperski et al, Topical minoxidil therapy for androgenetic alopecia.    A 30-month study. Arch Dermatol 1987 Nov 123:11 1483–7

1. A composition for inducing hair growth comprising a mixture ofextracts of saw palmetto and swertia, or their derivatives, or of activecomponents of said extracts in a concentration from 0.01% to 99.9% sawpalmetto extract and a concentration of 0.001% to 20% swertia and in aninternally ingested form selected from the group consisting of tablet,capsule, drops, and suspension.
 2. The composition of claim 1 whereinsaid mixture further comprises an extract for hair invigoration selectedfrom the group consisting of aloe vera, borage, chamomile, forsynthia,ginseng, grape seed, guarana, jojoba, kola, lavender, neetle root,polygonum (Fo-Ti), rosemary, pumpkin seed, pygeum, red clover, soy, teatree oil and thyme.
 3. The composition of claim 1 wherein said mixturefurther comprises a hair nourishment agent selected from the groupconsisting of vitamin A, B, C, D, E and zinc and its derivatives.
 4. Thecomposition of claim 1 wherein said mixture further comprises anantimicrobial agent.
 5. The composition of claim 1 wherein said mixturefurther comprises a nitric oxide donor.
 6. The composition of claim 1wherein said mixture further comprises a suitable carrier, solvent,emulgent or solution.
 7. A method of inducing hair growth in humans oranimals comprising treating the human or animal with a mixture of sawpalmetto extract and swertia extract in a concentration from 0.01% to99.9% saw palmetto extract and a concentration of 0.001% to 20% swertia,and in an internally ingested form selected from the group consisting oftablet, capsule, drops, and suspension.
 8. A composition for inducinghair growth comprising a mixture of extracts of saw palmetto andswertia, or their derivatives, or of active components of said extractsin a concentration from 1% to 50% saw palmetto extract and aconcentration of 0.2% to 5.0% swertia extract and in an internallyingested form selected from the group consisting of tablet, capsule,drops, and suspension.
 9. The composition of claim 8 wherein saidmixture further comprises an extract for hair invigoration selected fromthe group consisting of aloe vera, borage, chamomile, forsynthia,ginseng, grape seed, guarana, jojoba, kola, lavender, neetle root,polygonum (Fo-Ti), rosemary, pumpkin seed, pygeum, red clover, soy, teatree oil and thyme.
 10. The composition of claim 8 wherein said mixturefurther comprises a hair nourishment agent selected from the groupconsisting of vitamin A, B, C, D, E and zinc and its derivatives. 11.The composition of claim 8 wherein said mixture further comprises anantimicrobial agent.
 12. The composition of claim 8 wherein said mixturefurther comprises a nitric oxide donor.
 13. The composition of claim 8wherein said mixture further comprises a suitable carrier, solvent,emulgent or solution.
 14. A composition for inducing hair growthcomprising a mixture of extracts of saw palmetto and swertia, or theirderivatives, or of active components of said extracts in a concentrationfrom 5.0% to 25% saw palmetto extract and a concentration of 0.5% to2.0% swertia extract and in an internally ingested form selected fromthe group consisting of tablet, capsule, drops, and suspension.
 15. Thecomposition of claim 14 wherein said mixture further comprises anextract for hair invigoration selected from the group consisting of aloevera, borage, chamomile, forsynthia, ginseng, grape seed, guarana,jojoba, kola, lavender, neetle root, polygonum (Fo-Ti), rosemary,pumpkin seed, pygeum, red clover, soy, tea tree oil and thyme.
 16. Thecomposition of claim 14 wherein said mixture further comprises a hairnourishment agent selected from the group consisting of vitamin A, B, C,D, E and zinc and its derivatives.
 17. The composition of claim 14wherein said mixture further comprises an antimicrobial agent.
 18. Thecomposition of claim 14 wherein said mixture further comprises a nitricoxide donor.
 19. The composition of claim 14 wherein said mixturefurther comprises a suitable carrier, solvent, emulgent or solution.